Congestive heart failure (CHF) is a common syndrome characterized by decreased cardiac contractility, abnormal diastolic compliance, reduced stroke volume, and pulmonary congestion, as well as decreased cardiac output. CHF may be caused by many different etiologies whose clinical manifestations reflect a decrease in the myocardial contractile state such that cardiac output is reduced. The CHF disease state may arise, for example, from deficiencies in cardiac contractility, right ventricular failure, biventricular failure, systolic dysfunction, diastolic dysfunction, and pulmonary effects. In particular, CHF develops when plasma volume increases and fluid accumulates in the lungs, abdominal organs, and peripheral tissues (Beers and Berkow, eds., The Merck Manual of Diagnosis and Therapy, 17.sup.th ed. (Whitehouse Station, N.J.: Merck Research Laboratories, 1999) 1682-88).
Drug treatment for CHF primarily involves diuretics, ACE inhibitors, digitalis, and .beta.-blockers. In mild cases, thiazide diuretics, such as hydrochlorothiazide at 25-50 mg/day or chlorothiazide at 250-500 mg/day, are useful. However, supplemental potassium chloride is generally needed, since chronic diuresis causes hypokalemis alkalosis. Moreover, thiazide diuretics usually are not effective in patients with advanced symptoms of CHF. Typical doses of ACE inhibitors include captopril at 25-50 mg/day and quinapril at 10 mg/day. Numerous side effects are possible, though, including decreased blood pressure, renal insufficiency, potassium retention, and coughing. Digitalis preparations, particularly of digoxin, are widely prescribed in the United States, although the role of digitalis continues to be debated, and its usefulness in treating CHF in the absence of atrial fibrillation remains controversial. .beta.-blockers, too, must be used with caution when treating patients with CHF. A more indirect component of CHF management includes the recognition and control of factors that may be causing increased cardiac demands or adversely affecting myocardial function (e.g., hypertension, anemia, excess salt intake, excess alcohol, arrhythmias, thyrotoxicosis, fever, increased ambient temperature, or pulmonary emboli) (Beers and Berkow, eds., The Merck Manual of Diagnosis and Therapy, 17.sup.th ed. (Whitehouse Station, N.J.: Merck Research Laboratories, 1999) 1688-91). In view of the foregoing, many of the current methods available for treating CHF produce negative side-effects, or are only indirect. Accordingly, there currently exists a need for new and better methods for improving the survival of patients with CHF.
Triiodothyronine (T.sub.3) is a hormone synthesized in the thyroid gland. Along with tetraiodothyronine (T.sub.4), T.sub.3 is produced by the iodination and coupling of the amino acid tyrosine. T.sub.3 is known to enhance oxygen (O.sub.2) consumption by most tissues of the body, increase the basal metabolic rate, and influence the metabolism of carbohydrates, lipids, and proteins. While T.sub.4 is commonly administered in replacement or supplemental therapy to treat patients with most forms of hypothyroidism, T.sub.3 is only rarely administered because numerous complications are associated with its usage (as discussed below). In addition, T.sub.3 is used as a pituitary thyroid-stimulating hormone (TSH) suppressant, in the treatment or prevention of various types of euthyroid goiters. Finally, T.sub.3 is used as a diagnostic agent in suppression tests to differentiate suspected mild hyperthyroidism or thyroid gland autonomy (Physicians' Desk Reference, 54.sup.th ed. (Montvale, N.J.: Medical Economics Company, Inc., 2000) 1081, 1513).
Studies have also demonstrated that acute administration of T.sub.3 can result in increased cardiac performance and reduced systemic resistance in a number of clinical scenarios, including cardiac transplantation, cardiopulmonary bypass (Klemperer et al., N. Engl. J. Med., 333:1522-27, 1995), and myocardial ischemia (a deficiency of blood supply to the heart muscle, due to obstruction or constriction of coronary arteries) (Klein et al., Hosp. Formul., 28:848-58, 1993). Nevertheless, it is well-recognized that thyroid-hormone therapy should be used with great caution in a number of circumstances where the integrity of the cardiovascular system, particularly the coronary arteries, is suspected (Physicians' Desk Reference, 54.sup.th ed. (Montvale, N.J.: Medical Economics Company, Inc., 2000) 1082, 1513).
Indeed, the long-term or chronic administration of T.sub.3 has been historically contraindicated, due to concerns regarding oxygen-wasting effects, arrhythmia, and exacerbation of angina pectoris. In particular, the prevalent paradigm holds that T.sub.3 is not suitable for long-term treatment, as it increases O.sub.2 consumption by the heart without a concomitant increase in the blood supply: a classic scenario for the development of angina, fibrillation, and other heart conditions (Levine, H. D., Am. J. Med., 69:411-18, 1980; Klemperer et al., N. Engl. J. Med., 333:1522-27, 1995; and Klein and Ojamaa, Am. J. Cardiol., 81: 490-91, 1998). H. D. Levine (Am. J. Med., 69:411-18, 1980), for example, even suggested that the administration of thyroid hormone, and the return to a euthyroid state, would actually induce or exacerbate heart problems in patients with hypothyroidism and coronary disease.
The possible use of thyroid hormone to treat CHF was considered by Klein and Ojamaa in a review article (Am. J. Cardiol., 81: 490-91, 1998). The suggestion was based predominantly on an earlier study in which a single high dose of thyroid hormone was administered to improve cardiac performance in an acute setting. No evidence was provided to indicate that long-term administration of T.sub.3 could be successfully and safely used to treat CHF. The authors also expressly acknowledged that further research was necessary to ascertain the safety and efficacy of the use of T.sub.3 to treat CHF. In view of the known contraindications associated with the long-term administration of T.sub.3, the skilled artisan would not have had a reasonable expectation that T.sub.3 could be used to safely treat CHF.